Fluorinating reagents and method of fluorination

ABSTRACT

Fluorinating reagents expressed in a general formula; ##STR1## (In the general formula, R is an alkyl group having 1 to 5 carbons or a dialkylamino group in which each alkyl group has 1 to 3 carbons.), and a fluorinating method to fluorinate an alcoholic hydroxyl group by using the reagent. Raw materials of the aforesaid fluorinating reagents can be easily converted to object products and are less poisonous and corrosive. Their procurement and preparation are also easy. Further, it is easy to fluorinate compounds containing an alcoholic hydroxyl group by using this fluorinating reagents.

This invention relates to fluorinating reagents needed for producingcompounds containing fluorine which are important as medicines and theirintermediates and to the method of fluorination which uses thefluorinating reagent.

PRIOR ART

As reagents and methods of fluorinating an alcoholic hydroxyl group,following methods shown in (1) to (5) have been known so far.

(1) A method of fluorinating a hydroxyl group in secondary alcohol ortertiary alcohol by using HF or HF/pyridine solution (M. Hudlioky,"Chemistry of Organic Fluorine Compounds", 2nd ed., Ellis Hotwood Ltd.1976, page 689: G. A. Olah et al., Synthesis, 1973, page 786).

(2) A method in which after a hydroxyl group in alcohol is converted toan ester of sulfonio acid, the ester is fluorinated by making it reactwith alkalimetal fluoride including KF (M. Hudlicky, "Chemistry ofOrganic Fluorine Compounds", 2nd ed., Ellis Horwood Ltd. 1976, page689).

(3) A method of fluorinating a hydroxyl group by using fluoroalkylamineas a fluorinating reagent which is obtained from the reaction ofsecondary amine with ohlorotrifluoroethylene or hexafluoropropene (E. D.Bergmann et al., Isr. J. Chem., Vol. 8, page 925, 1970: Ishikawa et al.,"Chemistry of Organic Synthesis", Vol. 37, No.7, page 607, 1979).

(4) A method of fluorinating a hydroxyl group by using diethylaminosulfur trifluoride (DAST) as a fluorinating reagent (W. J. Middleton etal., "Org. Synthesis", Vol. 57, page 50, 1977).

(5) A method of fluorinating a hydroxyl group by using as a fluorinatingreagent difluorotriphenyl-phosphorane from the reaction oftriphenylphosphine with sulfur tetrafluoride (Kobayashi et al., "Chem.Pharm. Bull." (Tokyo), Vol. 16, page 1009, 1968).

The inventor of this invention studied new fluorinating reagents,especially those containing phosphorus, in place of the above-mentionedwell-known fluorinating reagents.

It is not easy to prepare the fluorinating reagent described in theabove (5), because very poisonous and corrosive sulfur tetra-fluoridemust be used as a raw material.

OBJECTS OF THE INVENTION

The object of this invention is to offer fluorinating reagentscontaining phosphorus which can be easily and safely synthesized.

Another object of this invention is to offer a method of efficientlyfluorinating an alcoholic hydroxyl group by using the fluorinatingreagent containing phosphorus.

THE CONSTITUTION OF THE INVENTION

As a result of eagerly repeating searches and studies of theabove-mentioned fluorinating reagents which contain phosphorus and areeasy to prepare, the inventor found thatfluoro-(1-pentafluoro-1-propenyl)-tributyl phosphorane (hereinafterabbreviated FPTBP) obtained from the reaction of hexafluoropropene(hereinafter abbreviated HFP) with tributyl phosphine (hereinafterabbreviated TBP) could be used as a fluorinating reagent to fluorinatean alcoholic hydroxyl group, having reached the success of completingthis invention.

That is, this invention relates to fluorinating reagents (e.g. FPTBP)expressed in a general formula; ##STR2##

(In the general formula, R is an alkyl group having 1 to 5 carbons or adialkyl-amino group in which each alkyl group has 1 to 3 carbons.)

This invention also offers a fluorinating method that is characteristicof substituting fluorine for the above-mentioned alcoholic hydroxylgroup by the reaction of the fluorinating reagent and an organiccompound containing an alcoholic hydroxyl group.

A fluorinating reagent in this invention, FPTBP, for example, is easilyproduced by the reaction of TBP and HFP in such a solvent as methyleneohioride, diethyl ether, and diethylene glycol dimethyl ether (See D. J.Burton et al., "J. Fluorine Chem." Vol 44 page 167, 1989).

In this case, several ways can be taken, such as a way in which HFP isblown into TBP dissolved in a solvent to make them react, a reactionunder normal pressure in which HFP is put into after being condensatedby cooling and is made react with TBP, and a way that after putting asolvent and TBP into an autoclave HFP is introduced under pressure tomake it react with TBP.

When synthesis of fluorinating reagents is carried out with the methodof this invention, besides the above-mentioned TBP, trialkylphosphines,including trimethylphosphine, triethylphosphine, and tripropylphosphine,or tris (dialkyl-amino) phosphines, including tris (dimethylamino)phosphine and tris (diethyl-amino) phosphine, can also be used.

Such various kinds of raw materials can be easily converted to objectproducts and are less poisonous and corrosive. And they are easilyprepared. Moreover, as TBP and its above-mentioned substitutes, and HFPare all easily available, those materials being on sale can be used asthey are.

By using one of the aforementioned phosphines, a fluorinating reagent,its R in the above-mentioned general formula is corresponding to that ofthe used phosphine, can be obtained.

A compound containing an alcoholic hydroxyl group to be fluorinated isadded in a fluorinating reagent such as FPTBP solution obtained in thisway.

The mixture is kept at the reaction temperature of -10°-100° C.,preferablly at 0°-80° C. and stirred, then a compound with substitutedfluorine for its hydroxyl group and 1,1,1,2,3-pentafluoropropene areproduced. The products can be separated from the reaction mixture bydistillation under normal or reduced pressure. The amount of FPTBP ispreferable to be more than the equivalent to a hydroxyl group to befluorinated.

As compounds having an alcoholic hydroxyl group which can be fluorinatedby using fluorinating reagents in this invention, though they are notparticularly limited, alcohols such as methanol, ethanol, propanol,isopropanol and octyl alcohol, and compounds having asteroid structurewith a hydroxyl group (various compounds except those having OH group ofoarboxylic acid) are considered.

THE POSSIBILITY OF UTILIZING THE INVENTION IN INDUSTRY

Since fluorinating reagents in this invention are those compoundsexpressed in the above-mentioned general formula, raw materials of thereagents can be easily converted to object products and are lesspoisonous and corrosive. Their procurement and preparation are alsoeasy. Further, it is easy to fluorinate compounds containing analcoholic hydroxyl group by using this fluorinating reagents.

EXAMPLE

The invention will be explained in detail in the following examples.

EXAMPLE 1

Twenty ml of diethyleneglycol dimethyl ether and 20.3 g of TBP were putin a 100 ml glass reaction vessel equipped with a gas introduction tubeand a condenser cooled by dry ice. With the mixture cooled at 5°-10° C.,HFP was introduced through the gas introduction tube. HFP introductionrate was controlled so that inner temperature didn't rise over 10° C.After 15 g of HFP had been introduced, the mixture was further stirredfor 1 hour at 5°-10° C.

Then, after replacing the gas introduction tube with a dropping funnel,4.6 g of ethyl alcohol was dropped while keeping the reactiontemperature at 5°-10° C. After the end of dropping, the reaction mixturewas returned to room temperature and stirred continuously. In the firstplace, 1,1,1,2,3-pentafluoropropene was produced. Then, monofluoroethanebegan to be produced when the reaction mixture was heated to 50°-55° C.and continuously stirred. After 5 hrs. heating and stirring, productswere collected in a cold trap cooled at -70° C. The weight of thecollected liquid was 17.5 g. Gas ohromatographio analysis showed thatthe liquid was composed of 74.3 wt % of 1,1,1,2,3-pentafluoropropene and25.7 wt % of monofluoroethane. According to the result, the yield ofmonofluoroethane was 94%.

Furthermore, a fluorinating reagent FPTBP produced by theabove-mentioned reaction of TBP and HFP;fluoro-(1-pentafluoro-1-propenyl)-tributyl phosphorane was identified by¹⁹ F-NMR and ³¹ P-NMR analysis. Monofluoroethane produced in thefluorinating reaction was also identified by ¹⁹ F-NMR and ¹ H-NMRanalysis, and by Mass analysis. All the analysis data showed the samevalues as those reported in literatures.

EXAMPLE 2

Instead of ethanol, 6 g of isopropanol was used in the same reaction asExample 1. As the result, the amount of the collected liquid was 17.2 g.Gas chromatographic analysis showed that the liquid was composed of 69.2wt % of 1,1,1,2,3-pentafluoropropene and 30.8 wt % of 2-fluoropropane.According to the result, the yield of 2fluoropropane was 85%.

I claim:
 1. A method for replacing a hydroxyl group in an alcohol byfluorine which comprises reacting the alcohol with a compound of theformula ##STR3## wherein R is a C₁₋₅ alkyl group or a di-C₁₋₃ alkylaminogroup.
 2. A method according to claim 1, wherein R is a C₁₋₅ alkylgroup.
 3. A method according to claim 1, wherein R is a di-C₁₋₃alkylamino group.
 4. A compound of the formula ##STR4## wherein each R'is a C₁₋₃ alkyl group.